Our long term goal is to develop and apply state-of-the-art computational methods to provide theoretical underpinnings of the histone code. Histone proteins that form the nucleosome core are subject to a variety of post-translational transformations. These histone modifications make up the histone code which extends the information in the genetic code and is emerging as an essential mechanism to regulate gene expression. Failure of appropriate histone modifications can lead to aberrant gene regulation and is implicated in human diseases, notably cancer. In spite of a current flurry of significant advances in experimental studies, there has been little theoretical understanding regarding how the histone code is written, i.e., how enzymes generate or remove these modifications. In this proposal, we mainly focus on two such important histone-modifying enzyme families: Class I and II histone deacetylases (HDACs), and histone lysine methyltransferases (HKMTs). The former are among the most promising targets for the development of anti-tumor drugs, while histone lysine methylation has been addressed in studies of age-related neurodegenerative disorders as well as cancer. Our theoretical approaches will center on the combined ab initio quantum mechanical and molecular mechanical (QM/MM) methods, which allow for accurate modeling of the chemistry at the enzyme active site while properly .including the effects of protein environment. In aim 1, we will characterize the catalytic mechanism for class I and II histone deacetylases. In aim 2, we will investigate HKMTs to provide detailed insights into how the product specificity of histone lysine methylation is achieved. In aim 3, new ab initio QM/MM methods will be developed to further improve its accuracy, efficiency and capability. These proposed studies will not only make fundamental contributions to this new and important area of molecular biology, but also should facilitate the design of novel mechanism-based drugs for diseases stemming from aberrant histone modifications.